The present invention is generally related to pharmaceutical compositions for treating or preventing bone condition. These pharmaceutical compositions may be used to induce bone and/or cartilage formation in wound healing and tissue repair.
The costs of treatment for orthopedic and craniofacial bone conditions represent a significant biomedical burden. According to the 2002 US Health Cost & Utilization Project, hospital costs for cranial surgery (craniotomies and craniectomies) and facial trauma reconstruction alone were estimated to be approximately $549 million and $400 million, respectively (Steiner, C., A. Elixhauser, and J. Schnaier, Eff Clin Pract, 2002. 5(3): p. 143-51). The hospital costs for orthopedic surgeries (both trauma and nontrauma) are likely even higher as the figure for orthopedic industry sales alone was estimated to be $13 billion in 2002 (Medical Technology Fundamentals, Merrill Lynch, 2003. p. 11).
Overall, the major problem encountered in the treatment of orthopedic and craniofacial bone conditions concerns the modulation of bone and/or cartilage formation. Preferably, bone formation can be increased under conditions in which it would be desirable to have more or accelerated bone formation as part of the treatment of certain conditions (e.g., orthopedic or craniofacial fracture repair, spinal fusion surgery, joint fusion surgery, injured osteoporotic bone) or as part of the prevention of certain conditions (e.g., fracture prevention in osteoporotic bone). For long bone fracture, it would be desirable to have accelerated endochondral bone formation by accelerating the cartilage to hypertrophy and replaced by bone. Even more preferably, bone formation can also be decreased under conditions in which it would be desirable to have decreased or inhibited bone formation as part of the treatment or prevention of certain conditions (e.g., craniosynostosis, a condition of premature calvarial overgrowth across sutures leading to premature suture fusion; heterotopic ossification, a condition of abnormal bone formation in ectopic locations). Similarly, it would be preferred to increase cartilage formation under conditions in which it would be desirable to have more or accelerated cartilage formation (e.g., joint resurfacing, temporomandibular joint reconstruction, articular disc repair, intervertebral disc repair and regeneration).
Many compositions have been described for the treatment of bone conditions (Table 1). Most, if not all, describe compositions that promote bone formation through osteoconductive and/or osteoinductive properties. It is well established in the art that compositions with osteoinductive properties are generally more efficacious at forming bone than those with osteoconductive properties; however, both are necessary for optimal bone formation (Table 1). The current “gold standard” composition for treatment of many bone conditions is autologous bone graft, which has both osteoinductive and osteoconductive properties. However, autograft harvest can be associated with significant donor site morbidity including pain, gait disturbance, thigh paresthesia for iliac crest donor sites (Laurie, S. W., et al. Plast Reconstr Surg, 1984. 73(6): p. 933-8). Thus, there is a critical need for better autograft alternatives. Of compounds with osteoinductive ability, the bone morphogenetic proteins (BMPs) have been extensively described. When coupled with an osteoconductive carrier, BMPs offer the greatest promise of equaling or even surpassing autograft for treatment of many bone conditions (Valentin-Opran, A., et al. Clin Orthop, 2002(395): p. 110-20).
However, the known functional heterogeneity of the BMPs (Ducy, P. and G. Karsenty, Kidney Int, 2000. 57(6): p. 2207-14; Wang, S., et al., Kidney Int, 2003. 63(6): p. 2037-49) and the high dose of BMPs required for osteoinduction may limit their use due to cost considerations and to unpredictable side effects such as maxillary sinus cyst formation (van den Bergh, J. P., et al., J Clin Periodontol, 2000. 27(9): p. 627-36). Consequently, there is an ongoing clinical and commercial need for alternative or complementary osteoinductive molecules to the BMPs to promote bone and/or cartilage formation. In addition, there is an ongoing clinical and commercial need for inhibiting bone and/or cartilage formation under specific conditions that is not addressed by the osteoinductive BMPs.
The embodiments described below address the above-identified problems and needs.